T cells play a central role in the human immune system, mediating the ability to discriminate foreign from self, directing less specific elements of the immune system and serving as a repository for immunologic memory (Heitger, et al., Blood 90:850-857 (1997)). The ability to produce T cells in vitro suitable for use in human patients would represent a significant advance in the treatment of immunodeficiencies, infections and malignancies. However, the unique requirements for T cell development have been difficult to replicate in vitro.
T cell differentiation involves an obligate period of development and education in the thymus, an organ that undergoes involution in late adolescence and maintains only a low level of activity in normal adults (Simpson, et al., Clin. Exp. Immunol. 19:2610265 (1975); von Gaudecker, Cell Tissue Res. 186:507-525 (1978)). Culture systems that mimic the thymus microenvironment and allow the production of T cells from bone marrow precursor cells have generally used animal or unrelated human tissues and this makes these systems unsuitable for the production of T cells for use in humans (Galy, et al., Immunity 3:459-473 (1975); Kingston, et al., Nature 317:811-813 (1985); Weijer, et al., Blood 99:2752-2759 (2002); McCune, et al., Science 241:1632-1639 (1988); Poznansky, et al., Nat. Biotechnol. 18:729-734 (2000); Gardner, et al., Exp. Hematol. 26:991-999 (1998); Rosenzweig, et al., Blood 87:4040-4048 (1996); Tagoh, et al., Blood 88:4463-4473 (1996); Yeoman, et al., Dev. Comp. Immunol. 20:241-263 (1996); Plum, et al., Blood 84:1587-1593 (1994); Krowka, et al., J. Immunol. 146:3751-3756 (1991); Freedman, et al., Nat. Med. 2:46-51 (1996); Rosenzweig, et al., J. Med. Primatol. 25:192-200 (1996)).
The features of the thymus that endow it with the unique capacity to generate T cells have been extensively studied. Epithelial cells, stromal cells, dendritic cells and lymphopoetic cytokines all appear to be required for the differentiation of bone marrow hematopoetic progenitor cells (bmHPC) into mature, functional T cells (Anderson, et al., Nat. Rev. Immunol. 1:31-40 (2001)). The three-dimensional architecture of the thymus is also critical to the process of T cell development (van Ewijk, et al., Semin. Immunol. 11:57-64 (1999)).
Although unique in their ability to support lymphocyte development, the resident cellular elements of the thymus bear striking similarities to the cells of the skin. Thymic epithelial cells express many of the same keratins as epidermal keratinocytes (Laster, et al., Differentiation 31:67-77 (1986)). Hassal's corpuscles, a product of medullar thymic epithelial cells, contain keratins identical to those found in the stratum corneum of skin. In fact, it could reasonably be argued that the major difference between the thymus and skin lies in their distinct three-dimensional architecture.